Mitosis is the cell division process used by eurkaryotic cells in order to support growth, repair, tissue regeneration, and/or to replace dead cells.
In cancer cells, regulation of mitosis is defective and this is why these cells divide anarchically and give rise to tumours. Thus, one effective therapeutic route to prevent the development of cancer consists in blocking the division of cancerous cells using molecules with anti-mitotic or other anti-cancer properties.
Nevertheless, current anti-mitotic molecules (paclitaxel, better known under the name taxol, or colchicine for example) act without cell specificity on all cells without distinction, thus causing many unwanted side effects. It is therefore essential to develop anti-mitotic molecules with fewer harmful effects.
Every tumour needs nutrients and oxygen in order to grow. These elements are provided by intratumoral blood vessels which result from a mechanism known as angiogenesis. In fact, if these vessels are absent, tumour cells undergo a cell necrosis process, and tumour growth slows down then stops. An example of another therapeutic route to combat cancer therefore consists in blocking the angiogenesis process by blocking the molecules controlling this mechanism.
The plurality of current anti-angiogenic molecules are specific to one angiogenic factor. This monospecificity gives rise to resistance phenomena. Inhibition of one angiogenic factor type produces expression of another type by angiogenic compensation mechanisms. It is therefore beneficial to have available anti-angiogenic molecules with a broad spectrum of activity against the factors implicated.
However, inhibition of the angiogenesis process alone is generally found to be insufficient to effectively block tumour growth. In addition, it does not block the formation of metastases.
It would therefore be extremely useful to have available new anti-cancer molecules capable of inhibiting both tumour cell proliferation and the angiogenesis process in the tumour. In fact, a recent study has shown that a combination of two therapeutic molecules, one anti-mitotic and the other anti-angiogenic, produces a synergetic effect and significantly increases the efficacy of overall treatment compared to treatment with only one of these molecules.
Heretofore, no molecule with both these effects, anti-mitotic and anti-angiogenic, has been reported.
Moreover, the majority of current anti-cancer agents are not truly specific to tumour cells and therefore also target healthy cells, thus giving rise to many, and at times serious, side effects. This problem has been resolved in some cases by the development of antibodies which target the surface molecules of some tumours. However, the use of antibodies poses other serious problems and the development of effective therapeutic antibodies that are non-toxic is a lengthy, uncertain and expensive procedure. Moreover, the production of antibodies on a large scale and under strict health and safety conditions is particularly difficult. As a result, treatments based on specific antibodies are still far and few between and extremely costly.
Another problem linked to conventional anti-cancer drugs, such as paclitaxel, is that these molecules are often highly hydrophobic which makes it necessary to develop complicated and expensive pharmaceutical formulations in order to achieve acceptable bioavailability in vivo. The problem of in vivo bioavailability is all the more acute in the case of treatment using nucleic acids since it is extremely difficult for them to reach their target cells in an efficacious and specific manner.
It would therefore be extremely useful to have available new anti-cancer molecules which present the following characteristics: much improved efficacy as a result of their dual inhibitory action on tumour proliferation and angiogenesis such that they can be effective alone, without the use of conventional chemotherapy or radiotherapy and thus greatly the limit side effects linked to these types of treatment, a fairly broad spectrum of activity against angiogenic factors to prevent resistance to treatment, very few side effects as a result of greater specificity towards tumour cells, a synthesis process that is easily adaptable to an industrial scale, easier to use, notably as a result of better bioavailability and/or longer half-life in vivo, in particular as a result of direct specificity for tumour cells, with good solubility in aqueous media and improved resistance to in vivo breakdown processes.
Thus, there is a need in the field for compositions and methods for the inhibition of detrimental forms of cell proliferation, and notably cancer cell growth.
WO2007/125210 discloses polyvalent or multivalent synthetic peptides made of at least three particular pseudopeptide units grafted to a support. This family of compounds (which have been named Nucant compounds), has been shown to interact with surface nucleolin RGG domain and to have both anti-proliferative and anti-angiogenic properties and to be useful for the treatment of cancer or inflammatory diseases. They have a fairly broad spectrum of activity against angiogenic factors, a good solubility in aqueous media, improved resistance to in vivo breakdown processes (due to the presence of a modified bond in pseudopeptide units), showed very few side effects, and have a synthesis process that is easily adaptable to an industrial scale. Specific exemplified compounds include compound HB19 and compounds Nucant 1, 2, 3, 6 and 7 (see FIG. 2 of this document). This document is herein incorporated in its entirety.
WO2009/141687 discloses improved Nucant compounds, in which lysine residues in the pseudopeptide units are all in the same L or D configuration. This document notably describes compound Nucant 6L (N6L), which corresponds to compound Nucant 6 as disclosed in WO2007/125210, in which all lysine residues of the pseudopeptide units are in L configuration. This compound showed improve anti-cancer activity compared to complex compound Nucant 6 in which the lysine residue of each pseudopeptide unit may be in L or D configuration. The compounds were also shown to improve wound healing. This document is herein incorporated in its entirety. WO2009/141687 also discloses compounds Nucant 4, 8 and 9 (see claim 10 of this document).
While the Nucant compounds disclosed in the two above mentioned documents are very interesting as such, it would still be desirable to further improve their anti-proliferative and anti-angiogenic properties. Indeed, this would permit to decrease the amount that would be therapeutically effective, thus decreasing the cost of treatment and further limiting side effects.